Phase 1
Batch Record Review
1Compile complete batch record package
Collect all documents required for release review before beginning the review process. Batch Manufacturing Record or executed batch record with all steps completed and signed. All in-process testing results. Deviation records and investigations related to this batch. Environmental monitoring data for the manufacturing period. Equipment calibration and cleaning records. Material certificates of analysis for all active and inactive components. Packaging and labelling records. The package must be complete - a release review cannot begin with missing records.
21 CFR 211.192 · 21 CFR 211.188 · EU GMP Chapter 4
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2Review batch manufacturing record completeness
Every step in the batch record must be completed, dated and signed by the performing operator and checked by a second person where required. Blank fields, undated entries, retrospective corrections without documentation and incomplete yield calculations are data integrity violations that prevent release. Electronic records must have complete audit trails. A batch record with unexplained blank fields or unsigned steps cannot be approved for release regardless of analytical results.
21 CFR 211.192 · ALCOA+ · 21 CFR Part 11 · EU GMP Annex 11
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3Verify component reconciliation and yield
Verify that the quantities of all components used in the batch are reconciled against the theoretical quantities per the batch record. Actual yield must be calculated and compared against theoretical yield with any discrepancies outside the acceptable range documented and investigated. Unexplained yield discrepancies are a 21 CFR 211.192 deficiency and a data integrity risk. Material reconciliation must account for all components including reject, rework and in-process sample quantities.
21 CFR 211.192 · 21 CFR 211.188(b)(7) · EU GMP Chapter 4
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Is the batch record complete, accurate and reconciled?
YES → Phase 2
NO → Hold - investigate
Phase 2
QC Testing Review
4Review all release specification test results
Every test in the release specification must have a result reported. Identity, assay, purity, related substances, physical attributes, microbiological testing, container closure integrity, water content, dissolution or disintegration as applicable. Results must be compared against approved specification limits. Each test result reviewed individually - not as a summary pass or fail. Raw data must be available and the analytical run must have met all system suitability criteria before the result is considered valid.
21 CFR 211.165(f) · 21 CFR 211.194 · EU GMP Chapter 6
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Are any results OOS or missing?
YES → OOS investigation required
NO → Step 5
↓ NO OOS
5Verify analytical method validity and system suitability
Confirm that the analytical methods used are validated and that system suitability criteria were met for each analytical run. A result obtained from a run that failed system suitability criteria is not a valid result. Confirm the reference standards used were within their expiry dates and were prepared per the approved procedure. Confirm that analyst training records are current for the methods used. An otherwise compliant analytical result obtained by an untrained analyst is a data integrity vulnerability.
21 CFR 211.165 · 21 CFR 211.194 · ICH Q2(R2)
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6Review stability data and shelf life confirmation
Confirm that stability data supporting the approved shelf life remains current. For batches where the registered stability protocol requires ongoing stability testing confirm that the stability samples for this batch have been pulled and placed on stability. Confirm that no adverse stability trending has occurred for this product type that would call the established shelf life into question. Stability data gaps or OOS stability results must be assessed before release.
21 CFR 211.166 · ICH Q1A(R2) · EU GMP Chapter 6
Phase 3
Quality Assessment
7Review all deviations and investigations
Every deviation that occurred during manufacture of this batch must be reviewed. Each deviation must have a completed investigation with a documented conclusion on batch impact. A deviation without a completed investigation cannot support release. The Quality Unit must specifically assess whether each deviation conclusion is adequate - not just whether a deviation record exists. An investigation that concludes no impact without documented rationale is as problematic as no investigation. All deviations must be closed and QA-approved before release can proceed.
21 CFR 211.192 · EU GMP Chapter 1 Section 1.8
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8Review environmental monitoring data
For sterile products review the environmental monitoring data for the manufacturing period. Confirm no action level exceedances occurred during or after the manufacturing session that would affect this batch. Confirm that all EM data from the manufacturing period has been received and reviewed - late EM data is a common cause of batch hold after provisional release. For non-sterile products review bioburden data where applicable and any EM data specified in the batch record or annual product quality review.
EU GMP Annex 1 2022 · 21 CFR 211.113 · USP 1116
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Are any deviations unresolved or EM data outstanding?
YES → Hold pending resolution
NO → Step 9
↓ NO
9Review packaging, labelling and serialisation
Confirm that packaging and labelling records are complete with reconciliation of labels used, labels destroyed and any overruns within limits. Label text confirmed against approved artwork and market authorisation. For products subject to serialisation requirements confirm that serialisation data has been uploaded and verified. Labelling errors are a leading cause of product recalls globally. The label review is a patient safety act not a clerical check.
21 CFR 211.122 · 21 CFR 211.125 · EU GMP Chapter 5
Phase 4
Disposition Decision
10Quality Unit or QP final assessment
The Quality Unit reviewer or QP performs a final holistic assessment of all review elements: batch record completeness and accuracy, component reconciliation, all specification results within limits, analytical method validity, deviation closure status, EM data review and packaging and labelling. The final assessment must be documented with the reviewer's conclusion and approval. In the EU the QP must personally confirm all Annex 16 obligations before signing the batch certificate. This is not a rubber stamp - it is a professional judgement with regulatory and legal weight.
21 CFR 211.22 · EU GMP Annex 16 · Directive 2001/83/EC
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Does the complete batch evidence package support release?
YES → Release
NO → Hold or Reject
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✓ RELEASED
QA or QP approval documented. Batch certificate issued. Release date recorded. Certificate of analysis generated.
21 CFR 211.22 · EU Annex 16
✗ REJECTED
Rejection documented with reason. Batch quarantined. CAPA opened. Scope extension to other batches assessed per 21 CFR 211.192.
21 CFR 211.192 · 21 CFR 211.165
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▶ ON HOLD
Pending investigation completion, EM data receipt, deviation closure or QP review. Documented hold reason with expected resolution date. No distribution during hold.
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11Post-release record retention
All batch records retained for the required period: 21 CFR 211.180(a) requires records be retained for at least 1 year after the expiry date or 3 years after distribution, whichever is longer. EU GMP requires records retained for at least 1 year after the shelf life of the batch or at least 5 years after certification, whichever is longer. Retain reference and retention samples per 21 CFR 211.170 and EU GMP Annex 19. Records must remain accessible and legible for the full retention period.
21 CFR 211.180(a) · 21 CFR 211.170 · EU GMP Annex 19
Batch Release Evidence Checklist - Quality Unit Minimum Review
Executed batch manufacturing record - all steps completed, signed and dated with no unexplained blank fields
Component reconciliation within approved limits with all discrepancies investigated and resolved
Actual yield versus theoretical yield calculated and within approved range or discrepancy investigated
All release specification test results within limits - identity, assay, purity, related substances, physical, microbiological
Analytical method validation current - no expired validations or specification changes without updated validation
All analytical runs met system suitability criteria - no runs with failed system suitability reported as valid
Reference standard certificates of analysis current and within expiry on date of use
All deviations during manufacture closed with QA-approved investigations and documented batch impact conclusions
No open OOS investigations for this batch - all OOS results either invalidated with documented evidence or investigated to conclusion
Environmental monitoring data for the manufacturing period received, reviewed and within limits or exceedances investigated
Equipment used for manufacture was in calibrated and qualified status at time of use
Cleaning validation status current for all shared equipment used in manufacture of this batch
Packaging and labelling records complete with label reconciliation within approved limits
Label text confirmed against current approved artwork and market authorisation text
Serialisation data uploaded and verified where applicable
Stability samples placed on stability and confirmed per approved protocol
No adverse stability trending for this product that would affect shelf life conclusion
Approved specifications and analytical methods used are those in the current approved regulatory submission
EU QP Certification - Key Personal Obligations (Annex 16)
Personal and non-delegable certification act
The QP must personally sign the batch certificate. The signature carries legal weight under Directive 2001/83/EC. The QP can delegate preparatory review activities to qualified staff but the certification act itself cannot be delegated. A QP who signs a certificate without personally assuring themselves of the requirements has not fulfilled their statutory obligations regardless of what subordinates have reviewed.
Manufacturing authorisation compliance
The QP must confirm the batch was manufactured at a site holding an appropriate Manufacturing Authorisation. For imported batches from third countries without an MRA the QP must ensure testing in the EU or EEA has been performed unless a recognised MRA exempts this requirement.
Marketing authorisation compliance
The QP must confirm that all manufacturing steps were carried out in accordance with the Marketing Authorisation. Any manufacturing that deviated from the approved MA without an appropriate variation is a certification risk for the QP regardless of product quality outcome.
Post-certification obligations
If the QP discovers after certification that a significant quality defect was not included in the batch documentation reviewed - such as the environmental monitoring exceedance case in this series - the QP has statutory obligations to notify the national competent authority. Personal legal liability does not end at the point of certification.